title: Smad3 inactivation and MiR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat.
abstract: Carvedilol, a nonselective β-adrenoreceptor antagonist, protects against myocardial injury induced by acute myocardium infarction (AMI). The mechanisms underlying the anti-fibrotic effects of carvedilol are unknown. Recent studies have revealed the critical role of microRNAs (miRNAs) in a variety of cardiovascular diseases. This study investigated whether miR-29b is involved in the cardioprotective effect of carvedilol against AMI-induced myocardial fibrosis. Male SD rats were randomized into several groups: the sham surgery control, left anterior descending (LAD) surgery-AMI model, AMI plus low-dose carvedilol treatment (1 mg/kg per day, CAR-L), AMI plus medium-dose carvedilol treatment (5 mg/kg per day, CAR-M) and AMI plus high-dose carvedilol treatment (10 mg/kg per day, CAR-H). Cardiac remodeling and impaired heart function were observed 4 weeks after LAD surgery treatment; the observed cardiac remodeling, decreased ejection fraction, and fractional shortening were rescued in the CAR-M and CAR-H groups. The upregulated expression of Col1a1, Col3a1, and α-SMA mRNA was significantly reduced in the CAR-M and CAR-H groups. Moreover, the downregulated miR-29b was elevated in the CAR-M and CAR-H groups. The in vitro study showed that Col1a1, Col3a1, and α-SMA were downregulated and miR-29b was upregulated by carvedilol in a dose-dependent manner in rat cardiac fibroblasts. Inhibition of ROS-induced Smad3 activation by carvedilol resulted in downregulation of Col1a1, Col3a1, and α-SMA and upregulation of miR-29b derived from the miR-29b-2 precursor. Enforced expression of miR-29b significantly suppressed Col1a1, Col3a1, and α-SMA expression. Taken together, we found that smad3 inactivation and miR-29b upregulation contributed to the cardioprotective activity of carvedilol against AMI-induced myocardial fibrosis.
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jie-Ning
authors.initials: JN
authors.lastname: Zhu
authors.forename: Ren
authors.initials: R
authors.lastname: Chen
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Fu
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Guo
authors.forename: Meng-Zhen
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Deng
authors.forename: Xiao
authors.initials: X
authors.lastname: Zou
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Zhong
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhuang
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Shan
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D000077261:Carvedilol; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D002227:Carbazoles; D002316:Cardiotonic Agents; C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; D011412:Propanolamines; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D000077261:Carvedilol